P1087: FAVEZELIMAB (ANTI–LAG-3) AND PEMBROLIZUMAB CO-BLOCKADE IN PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA WHO PROGRESSED AFTER ANTI–PD-1 THERAPY: AN OPEN-LABEL PHASE 1/2 STUDY
Authors: A. F. Herrera, D. Lavie, N. A. Johnson, A. Avigdor, P. Borchmann, C. Andreadis, A. Bazargan, G. Gregory, C. Keane, T. Inna, V. Vucinic, P. L. Zinzani, H. Zhang, P. Pillai, P. Marinello, J. Timmerman
Journal: HemaSphere (2022)

Background: PD-1 inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but optimal therapy is yet to be defined for patients whose disease progresses after anti–PD-1 treatment. Dual blockade of PD-1 and lymphocyte-activation gene 3 (LAG-3) has demonstrated antitumor activity in preclinical models. Aims: This multicohort phase 1/2 study (NCT03598608) evaluated safety and efficacy of favezelimab (MK-4280), a humanized IgG4 LAG-3 inhibitor, plus the PD-1 inhibitor pembrolizumab in patients with R/R hematologic malignancies. Cohort 2 focused on patients with R/R cHL refractory to anti–PD-1 therapy. Methods: This study included a safety lead-in phase (part 1) to determine recommended phase 2 dose (RP2D) followed by a dose-expansion phase (part 2). Eligible patients in cohort 2 had R/R cHL, relapsed after or were ineligible for autologous stem cell transplantation (ASCT), and progressed after ≥2 doses of anti–PD-1 therapy (within 12 weeks of last dose). In part 1, patients from all cohorts received intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W) and favezelimab IV 200 mg or 800 mg Q3W. Dose-finding based on occurrence of dose-limiting toxicities (DLT) was determined using a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D for up to 2 years (35 cycles), or until documented disease progression, adverse events (AEs), or withdrawal from study. Primary end point was safety, including DLTs and AEs. Secondary end point was objective response rate (ORR). Duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were exploratory end points. Results: Only 1 DLT (autoimmune hepatitis [grade 4]) was observed among the first 6 patients from all cohorts included in part 1 at the favezelimab 200 mg dose; thus, the dose was escalated to 800 mg. No DLTs were observed in the 15 additional patients at the 800 mg dose. Favezelimab RP2D was defined as 800 mg Q3W + pembrolizumab 200 mg Q3W. In cohort 2, 33 patients were enrolled; median age was 37 years, 64% had ECOG PS 0, and 94% had at least 4 prior lines of therapy. At database cutoff (Nov 1, 2021), 20 patients had discontinued treatment due to adverse events (n=7); disease progression or clinical progression (n=11); or withdrawal/physician decision (n=2). After a median follow-up of 16.5 months, ORR for patients receiving favezelimab 800 mg (n=29) was 31% (95% CI, 15-51; complete response, 2 [7%]; partial response, 7 [24%]). 19 of 29 responders (66%) had an anti–PD-1–based regimen as their most recent line of therapy at study entry. 23 of 29 patients (79%) had a reduction from baseline in target lesions. Median DOR for patients who received favezelimab 800 mg was not reached ([NR]; 95% CI, 0+ to 14+ months). For all patients in cohort 2, the median PFS was 9 months (95% CI, 5-15); 12-month PFS rate was 39%. Median OS was 26 months (95% CI, 26-NR); 12-month OS rate was 91%. Treatment-related AEs (TRAE) occurred in 28 patients (85%); most common (>10%) were hypothyroidism (18%), nausea and fatigue (15% each), and arthralgia and diarrhea (12% each). Grade 3 or 4 TRAEs occurred in 6 patients (18%) and 18% of patients discontinued treatment due to TRAEs. No treatment-related deaths occurred. Summary/Conclusion: Favezelimab 800 mg + pembrolizumab 200 mg Q3W showed a tolerable safety profile and effective antitumor activity in heavily pretreated patients with R/R cHL whose disease had progressed after anti–PD-1 therapy, suggesting that the combination may reinduce a response in these patients.